PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis (M.tb) is the causative agent of tuberculosis (TB) and the leading cause of death from a single infectious agent. An estimated 10 million people developed TB disease in 2017, demonstrating an urgent need to new therapeutic approaches, including host-directed therapy (HDT) to halt infection and progression of active TB. Macrophages often serve as the first line of defense against invading pathogens. However, M.tb modulates macrophage cell signaling pathways to induce an environment beneficial to its intracellular survival. The strategies employed by M.tb are an active area of investigation. The overall goal of the laboratory is to identify intracellular master regulators of inflammation and metabolic intermediates that dictate human macrophage responses to M.tb. Previous work in our lab revealed that M.tb interaction with the macrophage mannose receptor (MR) activates peroxisome proliferator-activated receptor gamma (PPAR?), a transcription factor that dampens the inflammatory response and is associated with increased M.tb growth. The proposed research plan will investigate the hypothesis that MR ligation by M.tb initiates the cAMP signaling pathway leading to PPAR? activation, resulting in enhanced survival of M.tb in macrophages. The Specific Aims are to: 1) Determine the role of phosphodiesterases (PDEs) in regulating PPAR? activity through the cAMP signaling pathway during M.tb infection of hMDMs, 2) Determine the role of Protein Kinase A (PKA) and Exchange Protein Directly Activated by cAMP 1 (Epac1) in regulating PPAR? activity following M.tb-elicited cAMP production in hMDMs, and 3) Determine the effects of MR/cAMP/PKA/Epac1/PPAR? signaling on M.tb pathogenesis. The proposed project will further elucidate the signaling pathway(s) downstream of MR ligation by M.tb, an area only minimally investigated. In addition, this project uses an innovative, newly developed humanized mouse model to study human MR in vivo devoid of the murine MR which is a confounding factor to data analysis. Investigation of the cAMP pathway is expected to identify new, druggable host cell targets for HDT against TB. This research plan affords me the ability to learn new scientific techniques, new models to study infectious diseases, detailed data analysis and the training to shape the direction of this project and my career. The training plan outlines career development activities including opportunities to improve my scientific presentation and communication skills, grantsmanship, mentoring and teaching skills. The research and training will take place at the Texas Biomedical Research Institute with a deep commitment to scientific training, evidenced by numerous journal clubs, seminars and full support of the Texas Biomed Association for Trainees. Texas Biomed has various core facilities, high containment research labs for M.tb work both in vitro and in mice and NHPs, and all resources needed for excellent scientific training. At fellowship completion, I will be prepared to lead a research program in host/pathogen interaction as an independent scientist.